Lipoxygenases, which are found in various mammalian tissues including the lung, mast cells, platelets, and white cells, are enzymes which oxidize arachidonic acid into hydroperoxyeicosatetraenoic acids (HPETEs) which are in turn reduced to the corresponding hydroxyeicosatetra-enoic acids (HETEs). The lipoxygenases are classified according to the position in the arachidonic acid which is oxygenated. Platelets metabolize arachidonic acid to 12-HETE via a 12-lipoxygenase, while polymorphonuclear leukocytes contain 5- and 15-lipoxygenases which oxidize arachidonic acid to 5-HPETE and 15-HPETE, respectively.
5-HPETE is the precursor of leukotriene A.sub.4, an unstable precursor of two distinct groups of leukotrienes. The first of these are the peptido-lipid leukotrienes LTC.sub.4 and LTD.sub.4 formed sequentially by reaction of LTA.sub.4 with glutathione followed by reaction with .gamma.-glutamyl trans-peptidase to form the cysteinylglycine adduct. These compounds account for the biologically active material known as the slow reacting substances of anaphylaxis (SRS-A).
These leukotrienes are potent smooth muscle contracting agents, particularly effective on smooth muscle but also on other tissues. They also promote mucous production, modulate vascular permeability changes and are potent inflammatory agents in human skin. The leukotrienes are potent spasmogens of human trachea, bronchus and lung parenchymal strips. Administered as an aerosol to normal volunteers, leukotrienes have been found to be about 3800 times more potent than histamine itself. In vitro studies have shown that antigen challenge of human lung or human mast cells results in the production and release of significant amounts of leukotrienes. For these reasons leukotrienes are thought to be major contributors of the symptoms of asthma and anaphylaxis. The most important compound of the second group of leukotrienes is leukotriene B.sub.4, a dihydroxy fatty acid. This compound is a potent chemotactic agent for neutrophils and in addition may modulate a number of other functions of these cells. It also affects other cell types such as lymphocytes and, for example, is thought to inhibit the phytohemagglutinin-induced elaboration of leukocyte inhibitory factor in T-lymphocytes. Leukotriene B.sub.4 is also a potent hyperalgesic agent in vivo and can modulate vascular permeability changes through a neutrophil-dependent mechanism.
Psoriasis is a human skin disease which affects from about 2 to 6 per cent of the population but fully adequate therapy remains unavailable. One of the earliest events in the development of psoriatic lesions is the recruitment of leukocytes to the skin site. In human psoriatic skin, abnormally high levels of free arachidonic acid and lipoxygenase products are found. Among these, leukotriene B.sub.4 has been identified in blister fluid from human psoriatic skin, and when injected into human skin, leukotriene B.sub.4 induces a pronounced accumulation of neutrophils at the site of injection. Moreover in humans with stable psoriasis, intralesional injection of 15-(S)-HETE, an inhibitor of 5- and 12-lipoxygenases, produces considerable improvement of psoriatic plates.
The leukotrienes are important mediators of inflammatory diseases through their ability to modulate leukocyte and lymphocyte functions. The presence of the leukotrienes is thought to be responsible for many of the symptoms observed in allergy and rheumatoid arthritis patients.
Applicants have now discovered a novel class of fluorinated arachidonic acid derivatives which are potent inhibitors of 5-lipoxygenase, the enzyme responsible for the conversion of arachidonic acid to the leukotrienes. These new compounds are useful as antiallergic and anti-inflammatory agents in the treatment of asthma, anaphylaxis, allergy, rheumatoid arthritis, psoriasis, and cardiovascular diseases.